This proposal seeks to develop a contrast-enhanced magnetic resonance imaging (MRI) method for imaging extracellular pH of tissues in vivo, with special emphasis on the kidneys. Perturbations of both renal and systemic pH may accompany diseases of the kidney such as renal tubular acidosis. The ability to image tissue pH, particularly renal pH, would be helpful to assess the extent and severity of such conditions, and also to non-invasively follow response to therapy in the affected tissue(s). GdDOTA-4AmP is a gadolinium-based MRI contrast agent with a pH-dependent longitudinal water-proton relaxivity. As with all other Gd-based contrast agents, the enhancement in water-proton relaxation rate produced by GdDOTA-4AmP is also dependent on its local concentration. In order to measure pH in vivo using GdDOTA-4AmP, one needs an independent measure of its pharmacokinetics in the animal being imaged. We propose a dual-contrast-agent strategy to image pH, in which GdDOTA-4AmP and a pH insensitive analogue, GdDOTP, are sequentially injected into the animal 1 h apart, with T1-weighted MRI images being dynamically collected following both injections. In preliminary experiments in mice we have made the assumption that the pharmacokinetics of GdDOTP and GdDOTA-4AmP are identical in a given animal, based on the similar size and charge of the two molecules. We have calculated preliminary pH images of the kidneys and surrounding tissues which distinctly show regions of acid pH corresponding to the collecting ducts, and pH 7.0-7.4 in other regions of the kidneys, in control mice. pH images of an acetazolamide-treated mouse showed an increase of 0.5-1.0 pH units in all renal pixels, with an apparent decrease of pH in extra-renal pixels, as compared to control mice. The goal of this proposal is to refine this dual-contrast-agent strategy for pH imaging using GdDOTA-4AmP and GdDOTP, and to characterize and minimize sources of error in the pH measurement.
The specific aims of this proposal are three-fold: (i) To optimize the dual-contrast-agent technique for imaging renal pH; (ii) To optimize the dual-contrast-agent technique for imaging pH of non-renal tissues; (iii) To devise a compromise protocol for optimally imaging pH of renal and non-renal tissues in the same experiment, and apply it to measure dose vs. pH response in mice with acetazolamide-induced acidosis.
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| Gillies, Robert J; Raghunand, Natarajan; Garcia-Martin, Maria L et al. (2004) pH imaging. A review of pH measurement methods and applications in cancers. IEEE Eng Med Biol Mag 23:57-64 |
